JP3105307B2 - Continuous production of solubilized β-carotene - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the continuous production of β-carotene solubilizates by a mixed chamber process.

[0002]

BACKGROUND OF THE INVENTION In the batch process described in EP-B 0 558 817, aqueous β-carotene solutions for injection are prepared using emulsifiers. For this, the emulsifier is heated to 170-180 ° C. and β-carotene is introduced into the melt. At this time, β-carotene dissolves with partial isomerization. After a residence time of about 6 minutes, the melt is cooled to 95.degree. C. and then water is initially introduced dropwise and the product is brought to an end with an active substance content of 4.5% by water. Adjust using. The emulsifier content is typically about 25%.

[0003] Due to the low solubility of β-carotene, the solubilizates must exhibit considerable stability with respect to recrystallization in storage tests, which is obtained with a favorable isomer ratio. Thus, the preparation of the products corresponding to this specification involves modulation of the isomerization. This is achieved only with difficulty in the described batch process.

[0004]

It is an object of the present invention to propose a continuous production process involving the control of the isomerization.

[0005]

SUMMARY OF THE INVENTION This object is achieved by heating β-carotene with an emulsifier for a short time to obtain a homogeneous solution, which is rapidly cooled to below 100 ° C. by the addition of water, followed by the desired final concentration. It has been found that this can be achieved by a continuous process for the preparation of β-carotene solubilisate by adjusting to β-carotene in the emulsifier, preheated to 20-80 ° C. Pumping the wt% suspension through a heating coil placed in a heat transfer oil (where the solubilized mixture is 120-180 ° C. and the residence time is 10-300 seconds); and Homogeneous solution at pressure 10
Mix turbulently at 10-80 ° C. with a considerable amount of water in a mixing chamber used at ５０50 bar,
Rapid cooling below 0 ° C. results in a solubilizer consisting of 0.5 to 6% by weight of β-carotene and, if necessary, dilution to the desired final concentration.

[0006] The mixing chamber may be T-shaped, in which water impinges on the β-carotene solution at an angle of about 180 °. The crucial point for the shape of the mixing chamber is to ensure turbulent mixing of the homogeneous solution and the aqueous phase.

A preferred emulsifier is HLB (HP feeder)
(Fiedler), Lexikon der Pharmazie, Kosmetik und angr
enzenden Gebiete, 1971, pages 263-270, especially pages 267-269) containing customary non-ionic emulsifiers having 12-16, especially ethoxylated oxyethylene units of fatty acids having 12-18 carbon atoms. Ethoxylated sorbitan fatty acid esters having about 20 triglycerides or oxyethylene units or ethoxylated monohydroxy fatty acids having 14 to 17 oxyethylene units as described in DE-A-291 12 241 It is. This type of emulsifier is also called a solubilizer. Since they promote the solubility of lipophilic substances by dissolving in water and thus retaining it in micellar solution. Micellar solutions are distinguished by clarity and clarity.
These are characterized by exhibiting micelle dimensions as measured by quasi-elastic light scattering. Depending on the solubilizer and active substance content used, the diameter is 10 to 10
0 nm.

Examples of particularly suitable non-ionic emulsifiers are: glycerol polyoxyethylene glycol ricinoleate, glycerol polyoxyethylene glycol hydroxystearate, polyoxyethylene (20) sorbitan monooleate, poly Oxypolyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate and monohydroxystearic acid having 15 units of oxyethylene.

The lysate is produced by a novel method, for example using an apparatus as shown in FIG. 1 as follows: The apparatus is divided into parts I, II and III. Part II is the hotter part, and the temperature of parts I and III is lower than 80 ° C.

Suspension of the concentration of β-carotene in the selected emulsifier, with or without 0.1-10% of antioxidants, of 1-40% by weight, preferably 10-30% by weight. The liquid is introduced into the container (1). Add this suspension to 20
８０80 ° C., preferably 60-70 ° C. The pump (2) continuously pumps the active substance suspension into the heating coil (3)
To supply. The heating coil is located in the heated heat transfer oil. The delivery of the pump (2), the length of the heating coil (3) and the temperature of the heat transfer oil were in each case between 120 and 180 ° C., the residence time of the suspension in the heating coil measured at the measuring point (9). The temperature is adjusted to 10 to 300 seconds (preferably 60 seconds). During this residence time, β-carotene dissolves in the solubilizer with simultaneous isomerization. The solution exiting the heating coil is turbulently mixed in the mixing chamber (6) with the aqueous phase which is likewise sent from the vessel (4) into the mixing chamber by the pump (5). A micellar β-carotene solution is produced in the mixing chamber. The aqueous phase is 10-80
° C, preferably 25 ° C. The aqueous phase may contain a preservative, for example benzyl alcohol, at a concentration of 0.5-5% of the final product. When the temperature of the solubilized substance downstream of the mixing chamber is measured at the measurement position (10), it is 40 to 80 ° C. The product is poured into a vessel (8) via a pressure regulator (7) adjusted to 10-50 bar. The content of active substance depends on the concentration and the flow rate chosen in each case and is usually from 0.5 to 6%, preferably 4%.

Examples of conventional antioxidants also used in the novel process are: butylated hydroxytoluene or hydroxyanisole and d, l-α-tocopherol. Antioxidants are generally used in amounts of 10 to 20% by weight, based on the β-carotene used.

It is also advantageous to use the customary accepted preservatives, for example: β-phenylethyl alcohol, β-phenoxyethyl alcohol and benzyl alcohol, especially benzyl alcohol.

The novel method can be used to produce a β-carotene solubilizate which provides a very stable solution for injection. The biological tolerability of injectable β-carotene lysates is higher than that of orally administered β-carotene. This high biological tolerability means that the maximum β-
Indicated by carotene concentration, which is for example in horses, cattle and pigs 10 to 100 times higher than after oral administration. β
-Injection of carotene lysate is used to improve the fertility of agricultural livestock such as horses, cattle, pigs and rabbits by increasing the rate of pregnant animals and the number of normal births.

The control of thermal isomerization in the novel process is achieved by selecting a dissolution temperature and a residence time which results in isomer ratios which are favorable for storage stability and physiological activity.

[0015]

EXAMPLES β-Carotene X in 250 g of 13-hydroxystearic acid and 10 g of butylated hydroxytoluene
g (see table) was placed in a container preheated to 70 ° C. This suspension was pumped to 2 l / h by a high pressure pump (2).
At a rate of 1 mm into a heating coil immersed in an oil bath. 2 mm inner diameter and 3 m length with heat transfer oil at about 160 ° C.
For 6m or 12m, the residence time is 17, 3 respectively.
It was set to 4 or 68 seconds. These times were in all cases sufficient to dissolve β-carotene in the emulsifier. After said residence time in the heating coil, the β-carotene solution is introduced into a T-type mixing chamber where it is brought to 180 ° C.
And turbulent mixing with 690 g of deionized water supplied at 5 l / h using a high pressure pump (5). At a pressure of 25 bar, the product was discharged via a pressure regulating valve. In all cases, a dark red micellar β-carotene solution resulted. The product was at 60 ° C. The active substance content was 4.3-5.5% depending on the method. The micelle diameter in the solubilizate measured by quasi-elastic light scattering is 2
It was 0 to 30 nm.

The following table shows the experimental parameters and measured data, including the measured isomer ratios.

Table Experiment No. 1 2 3 4 5 6 ──────────────────────────────────── β-carotene Weight [g] 50 50 42.5 42.5 42.5 50 Heating coil length [m] 3 12 12 3 6 6 Residence time [sec] 17 68 68 17 34 34 Temperature Solution [° C] 158 153-160 150 159 169 162 Solubilized material [° C] 58 57 60 60 61 64 Characteristics of solubilized product β-carotene content [wt%] 4.9 4.5 4.3 4.5 4.6 5.5 micelle size [nm] 30 ± 25% 21 ± 30 20 ± 22 20 ± 22 21 ± 20 22 ± 28 pH 7.0 6.9 7.0 6.7 7.0 6.7 Isomers content All-trans [% Note)] 66.4 36.9 38.0 56.6 50.6 Example 5 13-cis [% Note]] 18.1 21.7 20.7 23.2 17.5 and 9-cis [% Note]] 4.1 22.5 21.9 5.3 16.4 Same Note) Area% in HPLC at 450nm

[Brief description of the drawings]

FIG. 1 is an apparatus for producing a solubilized β-carotene.

[Explanation of symbols] 1 container, 2 pump, 3 heating coil,
4 container, 5 pump, 6 mixing chamber, 7 pressure regulator, 8 container, 9 thermometer, 10
thermometer

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Erik Ludecke, Germany Mutterstadt Thomas-Mann-Strasse 27 (72) Inventor Joachim Wu. Schneider Germany Weisenheim-Prowserstrasse 17 (72) Inventor Peter Paul Hoppe Germany Wachenheim am Hauenstein 13 (72) Inventor Friedrich-Wilhelm Lensmann Germany Bad-Dürkha im Phillip-Faut-Stra Case 6 (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 31/015 A61K 9/08 B01F 3/08 C07B 63/04 CA (STN)

Claims (1)

(57) [Claims] 1. Heating of β-carotene with an emulsifier for a short time to obtain a homogeneous solution, which is rapidly cooled to below 100 ° C. by addition of water and subsequently adjusted to the desired final concentration of β-carotene. In a continuous process for the preparation of β-carotene solubilizate, a suspension of 1-40% by weight of β-carotene in an emulsifier, preheated to 20-80 ° C., is placed in a heating coil Where the solubilized mixture is at 120-180 ° C. and the residence time is
10-300 seconds and the homogeneous solution is turbulently mixed with a considerable amount of water in a mixing chamber at 10-80 ° C.
A continuous process for producing a solubilized β-carotene, characterized in that a solubilized product containing 0.5 to 6% by weight of carotene is produced and, if necessary, diluted to a desired final concentration.